The broad, long-term objective of the proposed studies is to understand how gene regulation within progenitor cells affects the fate of cells that derive from these progenitors. Understanding how retina progenitors are regulated, in this case by a hormone, will contribute essential knowledge about these important cells that may aid in developing therapeutic interventions that aim to repair the damaged retina either by promoting an endogenous repair response, or by transplanting progenitor cells. In this application, the focus will be on how TH functions in retina progenitors to promote the ipsilateral projection in the frog Xenopus laevis. Capitalizing on multiple experimental advantages of this model organism, unique molecular insight into the regulation of progenitor cell and ganglion cell fate will emerge. The specific aims of this application are to: 1) determine the time and place of thyroid hormone action in controlling the development of the ipsilateral projection; 2) determine both whether a thyroid hormone regulated gene, Xmamdc2, which preliminary data show is expressed and functional in ipsilaterally projecting ganglion cells, functions in the turning of axons at the optic chiasm, and whether its function is similar or different from the known function of another class of axon guidance molecules, the EphBs; 3) determine whether a putative-transcription factor, Zic2, regulates the ipsilateral projection by regulating the expression of EphBs or Xmamdc2, and determine whether the action of Zic2 or other thyroid hormone regulated genes is mediated by their expression in either progenitor cells or differentiated ganglion cells. To meet these aims, the ipsilateral projection will be assayed by quantitative retrograde and anterograde labeling methods. Hundreds of transgenic animals will be made with plasmid and BAC transgenes in order to express gene products in the entire nervous system, only in the eye, or specifically to progenitor cells or ganglion cells. These studies will yield novel insight as to how the ipsilateral retinothalamic projection forms, will reveal a novel mechanism involved in axon guidance, and will uncover the mechanism by which thyroid hormone regulates the fate of retina progenitor cells. Though the experiments will be performed in Xenopus, the findings will be applicable to other vertebrates, including mammals.